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Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia

Molecular Psychiatry (2024)Cite this article

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Abstract

Deficient gamma oscillations in prefrontal cortex (PFC) of individuals with schizophrenia appear to involve impaired inhibitory drive from parvalbumin-expressing interneurons (PVIs). Inhibitory drive from PVIs is regulated, in part, by RNA binding fox-1 homolog 1 (Rbfox1). Rbfox1 is spliced into nuclear or cytoplasmic isoforms, which regulate alternative splicing or stability of their target transcripts, respectively. One major target of cytoplasmic Rbfox1 is vesicle associated membrane protein 1 (Vamp1). Vamp1 mediates GABA release probability from PVIs, and the loss of Rbfox1 reduces Vamp1 levels which in turn impairs cortical inhibition. In this study, we investigated if the Rbfox1-Vamp1 pathway is altered in PVIs in PFC of individuals with schizophrenia by utilizing a novel strategy that combines multi-label in situ hybridization and immunohistochemistry. In the PFC of 20 matched pairs of schizophrenia and comparison subjects, cytoplasmic Rbfox1 protein levels were significantly lower in PVIs in schizophrenia and this deficit was not attributable to potential methodological confounds or schizophrenia-associated co-occurring factors. In a subset of this cohort, Vamp1 mRNA levels in PVIs were also significantly lower in schizophrenia and were predicted by lower cytoplasmic Rbfox1 protein levels across individual PVIs. To investigate the functional impact of Rbfox1-Vamp1 alterations in schizophrenia, we simulated the effect of lower GABA release probability from PVIs on gamma power in a computational model network of pyramidal neurons and PVIs. Our simulations showed that lower GABA release probability reduces gamma power by disrupting network synchrony while minimally affecting network activity. Finally, lower GABA release probability synergistically interacted with lower strength of inhibition from PVIs in schizophrenia to reduce gamma power non-linearly. Together, our findings suggest that the Rbfox1-Vamp1 pathway in PVIs is impaired in schizophrenia and that this alteration likely contributes to deficient PFC gamma power in the illness.

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Fig. 1: Cytoplasmic Rbfox1 isoform is enriched in PVIs in human PFC.
Fig. 2: Protein levels of cytoplasmic Rbfox1 in PVIs are lower in PFC of schizophrenia.
Fig. 3: Lower cytoplasmic Rbfox1 levels in PVIs in schizophrenia are not due to methodological confounds or schizophrenia-associated co-occurring factors.
Fig. 4: Lower cytoplasmic Rbfox1 protein level predicts lower Vamp1 mRNA level in PVIs.
Fig. 5: Lower release probability of GABA from PVIs reduces gamma power in a computational model network.

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Code availability

All imaging analyses and computational simulations were performed in MATLAB. All codes are available upon request.

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Acknowledgements

We thank Kelly Rogers (University of Pittsburgh) for providing technical assistance. The University of Pittsburgh holds a Physician-Scientist Institutional Award from the Burroughs Wellcome Fund (Y.C.). This work was also supported by National Institutes of Health Grants MH103204 (D.A.L.) and MH043784 (D.A.L.).

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Authors and Affiliations

  1. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Youjin Chung, Samuel J. Dienel, Matthew J. Belch, Kenneth N. Fish, David A. Lewis & Daniel W. Chung

  2. Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA

    Samuel J. Dienel

  3. Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA

    G. Bard Ermentrout

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Chung, Y., Dienel, S.J., Belch, M.J. et al. Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02417-8

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